There is a large global burden of drug-resistant (DR) tuberculosis (TB) in children. Outcomes of children treated with individualized regimens are good, but treatment regimens are long and associated with substantial adverse effects. There are few child friendly formulations of the second-line drugs, which are poorly palatable, have significant side-effects, and for which there is limited pharmacokinetic (PK) data in children. The key second-line drugs levofloxacin, moxifloxacin, and linezolid will remain important in future treatment for DR-TB in children and adults; therefore data on the PK and optimal dose, safety, and acceptability of these medications is urgently needed. Building on our existing research, using a multi-disciplinary approach and state of the art methods, we aim to address critical knowledge gaps to guide the optimal, safe and child-friendly use of key 2nd line TB drugs in children, in order to improve existing MDR-TB treatment in children, inform development of child-friendly formulations, and to ensure timely pediatric access to novel regimens. Our specific aims are: 1: Using modelled optimized weight-banded doses, to determine drug exposure of levofloxacin, moxifloxacin, and linezolid in children with MDR-TB of representative ages; 2. To determine the safety of 2nd-line TB drugs in children with MDR-TB; 3. To investigate the effect of formulation (crushed versus whole tablets) on the acceptability and bioavailability of 2nd-line TB drugs in children with MDR-TB. To achieve these aims, we will conduct a prospective, longitudinal observational PK study in HIV-infected and uninfected children aged 0-17 years who are receiving routine treatment for DR-TB with moxifloxacin, levofloxacin, or linezolid. We will enrol 100 children over 2.5 years, in representative age strata enriched in younger age groups, for semi-intensive and sparse PK sampling, and concurrent assessments of treatment response, safety, bioavailability, and drug acceptability. Using population PK modelling techniques, we will model optimized doses of levofloxacin, moxifloxacin, and linezolid which approximate drug exposures in TB treated adults, and evaluate the PK, short (QT interval prolongation) and long-term safety, and acceptability of those doses in pragmatic weight bands in our cohort of children with DR-TB. We will follow children until completion of treatment, carefully documenting their bacteriologic, clinical, and radiological response to treatment in addition to their final outcome. We will explore associations between PK and treatment response and adverse effects. This study will impact the treatment of children with MDR-TB globally by informing the more optimal, safe, and acceptable use of these key 2nd-line TB drugs in children now and in the future.